Several aspects of normal aging and dementia of various types, emphasizing Alzheimer's disease, are to be investigated in this Program Project. P. Fuld is in charge of a psychometric analysis of a large group of in- and out-patients, many of whom ultimately come to autopsy. She also does psychometric assays on patients in L. Thal's treatment trials. The latter involve the cholinomimetic drugs physostigmine and tetrahydroaminoacridine. With the former, preliminary results are strongly positive and correlate with the degree of choline esterase inhibition in CSF. E. Buschke does psychologic studies on memory processing and retraining. R. Terry will do extensive neuropathologic studies on autopsy specimens entering the study so that appropriately evaluated tissue can be distributed to the collaborating investigators. He will also count neocortical and subcortical neurons and glia as well as plaques and tangles in various types of dementia, and will, by immunocytochemical techniques, map neuropeptides, somatostatin, substance P, vasopressin, and choline acetyltransferase in CNS. P. Davies will do 16 assays on neurotransmitters, their metabolic products and related enzymes (relevant to acetylcholine, four peptides, GABA, dopamine, norepinephrine, and serotonin) on tissue from multiple sites of human CNS specimens, and will be studying the control of somatostatin release in relation to cholinergic agents in neuroblastoma cells in culture. S.-H. Yen will examine the biochemical properties of proteins and their cross-linkages making up neurofibrillary tangles. J. Goldman will examine contractile proteins in the aging CNS, since they are involved in the Hirano body and might also have to do with determining shape and extent of neurites. Analyses involve psychometrics, light and electron microscopy, computerized image analysis morphometry, immunocytochemistry, enzyme assays, radio-immuno-assay and high pressure liquid chromatography. Normal aging rats, cell cultures, and autopsied human brain tissue are utilized. Mice and rabbits are used in preparing antisera.